Windows into stress: a glimpse at emerging roles for CRHPVN neurons.

The corticotropin-releasing hormone cells in the paraventricular nucleus of the hypothalamus (CRHPVN) control the slow endocrine response to stress. The synapses on these cells are exquisitely sensitive to acute stress, leveraging local signals to leave a lasting imprint on this system. Additionally, recent work indicates that these cells also play key roles in the control of distinct stress and survival behaviors. Here we review these observations and provide a perspective on the role of CRHPVN neurons as integrative and malleable hubs for behavioral, physiological, and endocrine responses to stress.

Particle-swarm based modelling reveals two distinct classes of CRHPVN neurons.

Electrophysiological recordings can provide detailed information of single neurons' dynamical features and shed light on their response to stimuli. Unfortunately, rapidly modelling electrophysiological data for inferring network-level behaviours remains challenging. Here, we investigate how modelled single neuron dynamics leads to network-level responses in the paraventricular nucleus of the hypothalamus (PVN), a critical nucleus for the mammalian stress response. Recordings of corticotropin releasing hormone neurons from the PVN (CRHPVN ) were performed using whole-cell current-clamp. These, neurons, which initiate the endocrine response to stress, were rapidly and automatically fit to a modified adaptive exponential integrate-and-fire model (AdEx) with particle swarm optimization (PSO). All CRHPVN neurons were accurately fit by the AdEx model with PSO. Multiple sets of parameters were found that reliably reproduced current-clamp traces for any single neuron. Despite multiple solutions, the dynamical features of the models such as the rheobase, fixed points, and bifurcations, were shown to be stable across fits. We found that CRHPVN neurons can be divided into two subtypes according to their bifurcation at the onset of firing: CRHPVN -integrators and CRHPVN -resonators. The existence of CRHPVN -resonators was then directly confirmed in a follow-up patch-clamp hyperpolarization protocol which readily induced post-inhibitory rebound spiking in 33% of patched neurons. We constructed networks of CRHPVN model neurons to investigate the network level responses of CRHPVN neurons. We found that CRHPVN -resonators maintain baseline firing in networks even when all inputs are inhibitory. The dynamics of a small subset of CRHPVN neurons may be critical to maintaining a baseline firing tone in the PVN. KEY POINTS: Corticotropin-releasing hormone neurons (CRHPVN ) in the paraventricular nucleus of the hypothalamus act as the final neural controllers of the stress response. We developed a computational modelling platform that uses particle swarm optimization to rapidly and accurately fit biophysical neuron models to patched CRHPVN neurons. A model was fitted to each patched neuron without the use of dynamic clamping, or other procedures requiring sophisticated inputs and fitting algorithms. Any neuron undergoing standard current clamp step protocols for a few minutes can be fitted by this procedure The dynamical analysis of the modelled neurons shows that CRHPVN neurons come in two specific 'flavours': CRHPVN -resonators and CRHPVN -integrators. We directly confirmed the existence of these two classes of CRHPVN neurons in subsequent experiments. Network simulations show that CRHPVN -resonators are critical to retaining the baseline firing rate of the entire network of CRHPVN neurons as these cells can fire rebound spikes and bursts in the presence of strong inhibitory synaptic input.

Sex-Specific Vasopressin Signaling Buffers Stress-Dependent Synaptic Changes in Female Mice.

In many species, social networks provide benefit for both the individual and the collective. In addition to transmitting information to others, social networks provide an emotional buffer for distressed individuals. Our understanding about the cellular mechanisms that contribute to buffering is poor. Stress has consequences for the entire organism, including a robust change in synaptic plasticity at glutamate synapses onto corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN). In females, however, this stress-induced metaplasticity is buffered by the presence of a naive partner. This buffering may be because of discrete behavioral interactions, signals in the context in which the interaction occurs (i.e., olfactory cues), or it may be influenced by local signaling events in the PVN. Here, we show that local vasopressin (VP) signaling in PVN buffers the short-term potentiation (STP) at glutamate synapses after stress. This social buffering of metaplasticity, which requires the presence of another individual, was prevented by pharmacological inhibition of the VP 1a receptor (V1aR) in female mice. Exogenous VP mimicked the effects of social buffering and reduced STP in CRHPVN neurons from females but not males. These findings implicate VP as a potential mediator of social buffering in female mice.SIGNIFICANCE STATEMENT In many organisms, including rodents and humans, social groups are beneficial to overall health and well-being. Moreover, it is through these social interactions that the harmful effects of stress can be mitigated, a phenomenon known as social buffering. In the present study, we describe a critical role for the neuropeptide vasopressin (VP) in social buffering of synaptic metaplasticity in stress-responsive corticotropin-releasing hormone (CRH) neurons in female mice. These effects of VP do not extend to social buffering of stress behaviors, suggesting this is a very precise and local form of sex-specific neuropeptide signaling.

Novel regulator of vasopressin secretion: phoenixin.

The newly described hypothalamic peptide, phoenixin, is produced in the hypothalamus and adenohypophysis, where it acts to control reproductive hormone secretion. Both phoenixin and its receptor GPR173 are expressed in the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei, suggesting additional, nonreproductive effects of the peptide to control vasopressin (AVP) or oxytocin (OT) secretion. Hypothalamo-neurohypophysial explants released AVP but not OT in response to phoenixin. Intracerebroventricular administration of phoenixin into conscious, unrestrained male and female rats significantly increased circulating AVP, but not OT, levels in plasma, and it increased immediate early gene expression in the supraoptic nuclei of male rats. Bath application of phoenixin in hypothalamic slice preparations resulted in depolarization of PVN neurons, indicating a direct, neural action of phoenixin in the hypothalamus. Our results suggest that the newly described, hypothalamic peptide phoenixin, in addition to its effects on hypothalamic and pituitary mechanisms controlling reproduction, may contribute to the physiological mechanisms regulating fluid and electrolyte homeostasis.

Sex-specific differences in cardiovascular and metabolic hormones with integrated signalling in the paraventricular nucleus of the hypothalamus.

NEW FINDINGS: What is the topic of this review? We describe roles of crucial signalling molecules in the paraventricular nucleus of the hypothalamus and highlight recent data suggesting sex-specific changes in the expression of crucial signalling molecules and their receptors, which may underlie sex differences in both cardiovascular and metabolic function. What advances does it highlight? This review highlights the integrative capacity of the paraventricular nucleus in mediating cardiovascular and metabolic effects by integrating information from multiple signalling molecules. It also proposes that these signalling molecules have sex-specific differential gene expression, indicating the importance of considering these differences in our ongoing search to understand the female-male differences in the regulation of crucial autonomic systems. Many traditional cardiovascular hormones have been implicated in metabolic function. Conversely, many hormones traditionally involved in metabolic regulation have an effect on cardiovascular function. Many of these signalling molecules exert such effects through specific actions in the paraventricular nucleus, an integrative autonomic control centre located in the hypothalamus. Here, we focus on four cardiovascular/metabolic peptide hormones that signal within the paraventricular nucleus, namely angiotensin II, orexin, adiponectin and nesfatin-1. Each of these hormones has specific electrophysiological effects on paraventricular nucleus neurons that can be related to its physiological actions. In addition, we introduce preliminary transcriptomic data indicating that the genes for some of these hormones and their receptors have sex-specific differential expression.

Adropin acts in the rat paraventricular nucleus to influence neuronal excitability.

Adropin is a peptide hormone with cardiovascular and metabolic roles in the periphery, including effects on glucose and lipid homeostasis. Central administration of adropin has been shown to inhibit water intake in rats; however, the site at which central adropin acts has yet to be elucidated. The hypothalamic paraventricular nucleus (PVN), a critical autonomic control center, plays essential roles in the control of fluid balance, energy homeostasis, and cardiovascular regulation, and is, therefore, a potential target for centrally acting adropin. In the present study, we used whole cell patch-clamp techniques to examine the effects of adropin on the excitability of neurons within the PVN. All three neuronal subpopulations (magnocellular, preautonomic, and neuroendocrine) in the PVN were found to be responsive to bath-application of 10 nM adropin, which elicited responses in 68% of cells tested (n = 57/84). The majority of cells (58%) depolarized (5.2 ± 0.3 mV; n = 49) in response to adropin, whereas the remaining responsive cells (10%) hyperpolarized (-3.4 ± 0.5 mV; n = 8), effects that were shown to be concentration-dependent. Additionally, responses were maintained in the presence of 1 µM TTX in 75% of cells tested (n = 9/12), and voltage-clamp analysis revealed that adropin had no effect on the amplitude or frequency of excitatory or inhibitory postsynaptic currents (EPSCs and IPSCs) in PVN neurons, suggesting the peptide exerts direct, postsynaptic actions on these neurons. Collectively, these findings suggest central adropin may exert its physiological effects through direct actions on neurons in the PVN.